The major cause of heart failure is the regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient for repair, recent efforts have focused on replacement of the lost cells using a variety of treatment options. Superoxide production following infarction contributes significantly to cell death of the adult myocytes and local stem cell populations. While direct injection of proteins may give some benefit, rapid diffusion and short half-lives limit their use clinically. The objective of this proposal is to encapsulate superoxide dismutase (SOD), a powerful endogenous scavenger of superoxide, within polyketal particles to enhance myocardial retention and improve function following infarction. Gene therapy and knockout mouse studies demonstrate a clear potential of SOD to treat cardiac dysfunction following myocardial infarction;however, the short half-life of the protein has limited its use clinically. Polyketal particles are a new class of polymers that are stable, degrade in to FDA- approved compounds, can be modified easily and can encapsulate proteins while retaining activity. The central hypothesis of this proposal is that polyketal particles can be used to deliver SOD in a quantifiable manner to reduce superoxide production following myocardial infarction. This reduction will lead to decreased cell death of adult myocytes, as well as preserve the local stem cell populations. In addition, this proposal will also test the hypothesis that SOD within polyketals can serve as an adjunct treatment to improve the efficacy of cell therapy. The successful completion of this R21 proposal will demonstrate that polyketal particles loaded with SOD can be used to treat cardiac dysfunction following myocardial infarction. Furthermore, polyketals have the ability to encapsulate small molecule inhibitors, DNA and proteins. Given the complicated endogenous response following myocardial infarction, we believe that data from this proposal will generate widespread interest in using polyketals for myocardial drug delivery. NARRATIVE: Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to encapsulate and deliver superoxide dismutase, an unstable antioxidant with therapeutic potential, directly to the myocardium using a new class of polymers called polyketals. This proposal will demonstrate that polyketals containing antioxidant proteins can be used to help regenerate cardiac tissue following myocardial infarction.